Science Weekly: End of the world news

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The BBC’s David Shukman, the Guardian’s hack day, mobile phone masts and cancer, and patenting genes

New Readers

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Easier Way to Synthesize New Drugs Could Have a Big Impact on Pharma Business

Some drugs may be more effective the longer they last inside the 1) ___. To prevent such drugs from being broken down too rapidly, pharmaceutical manufacturers often attach a fluorine-containing structure called a trifluoromethyl (CF3) group. However, the processes now used require harsh reaction conditions or only work in a small number of cases, limiting their usefulness for synthesizing new drug candidates for testing. Now, MIT chemists have designed a new way to attach a CF3 group to certain compounds, which they believe could allow pharmaceutical companies to create and test new drugs much faster and potentially reduce the cost of drug discovery. The new synthesis, reported in the June 25 issue of Science, could have an immediate impact. MIT Chemistry Professor Stephen Buchwald, who led the research team, says achieving the synthesis has been a long-standing challenge for 2) ___. The CF3 group  is a component of several commonly used drugs, including the antidepressant Prozac, arthritis medication Celebrex and Januvia, used to treat diabetes symptoms. When foreign compounds such as drugs enter the body, they get sent to the 3) ___, where they are broken down and shipped on to the kidneys for excretion. However, CF3 groups are hard for the body to break down because they contain three fluorine atoms. Fluorine is not really a component of things we eat, so the body does not know what to do with it. CF3 groups are also a common component of agricultural chemicals such as pesticides. To add a CF3 group to organic (carbon-containing) molecules, chemists often use hydrogen fluoride under conditions that might produce undesired reactions among the many structural components found in complex molecules like 4) ___ or agrochemicals. With the new reaction, the CF3 group can be added at a much later stage of the overall drug synthesis. The reaction can also be used with a broad range of starting materials, giving drug developers much more flexibility in designing new compounds. Chemists have been trying to find a widely applicable catalytic method to attach CF3 to aryl compounds (compounds containing one or more six-carbon rings) for a couple of decades. Some have achieved different parts of the reaction, but none successfully put all the pieces together to arrive at a method that is applicable for a wide range of different aryl 5) ___. The major challenge has been finding a suitable catalyst (a molecule that speeds up a reaction) to transfer the CF3 entity from another source to the carbon ring. CF3- tends to be unstable when detached from other molecules, so the catalyst must act quickly to transfer the CF3 group before it decomposes. The MIT team chose to use a catalyst built from palladium, a silvery-white metal commonly used in catalytic converters. The MIT team is not the first to try palladium catalysis for this reaction, but the key to their success was the use of a ligand called BrettPhos, which they had previously developed for other purposes. A ligand is a 6) ___ that binds to the metal to stabilize it and hasten the reaction. Coming up with a useful reaction required much testing of different combinations of palladium, ligand, CF3 source, temperature and other factors. Everything had to match up. During the reaction, a CF3 group is transferred from a silicon carrier to the palladium, displacing a chlorine atom. Subsequently, the aryl-CF3 unit is released and the catalytic cycle begins anew. The researchers tried the synthesis with a variety of aryl compounds and achieved yields ranging from 70 to 94% of the trifluoromethylated products. In its current state, the process is too expensive for manufacturing use. For drug discovery, however, it may lower overall 7) ___ because it streamlines the entire synthesis process. For discovery chemistry, the price of the metal is much less important. All of the reaction components are commercially available, so pharmaceutical and other companies will immediately be able to use this method. “This versatile new methodology is directly applicable to drug development,“ says John Schwab, a program director at the National Institute of Health’s National Institute of General Medical Sciences, which partially funded the research. “This is a terrific example of how U.S. healthcare consumers are benefiting from their investment in NIH and in basic, 8) ___ research.“ 

ANSWERS: 1) body; 2) chemists; 3) liver; 4) pharmaceuticals; 5) compounds; 6) molecule; 7) costs; 8) biomedical

Source: MIT: Journal Reference: Eun Jin Cho, Todd D. Senecal, Tom Kinzel, Yong Zhang, Donald A. Watson, Stephen L. Buchwald. The Palladium-Catalyzed Trifluoromethylation of Aryl Chlorides. Science, 2010; 328 (5986): 1679-1681 DOI: 10.1126/science.1190524

Lupus

Four main types of lupus exist: systemic lupus erythematosus, discoid lupus erythematosus, drug-induced lupus erythematosus and neonatal lupus erythematosus. Of these, systemic lupus erythematosus (SLE) is the most common and serious form of lupus. The history of SLE can be divided into three periods: classical, neoclassical, and modern.

The classical period began when the disease was first recognized in the Middle Ages and when a description of the dermatological manifestation of the disorder was recorded.  The term lupus (Latin for wolf) is attributed to 12th-century physician Rogerius, who used it to describe erosive facial lesions that were reminiscent of a wolf’s bite, and the classic malar rash, that resembled a wolf’s scratch. The first published illustrations of lupus erythematosus were included in von Hebra’s text, Atlas of Skin Diseases, published in 1856.

The neoclassical period was heralded by Moric Kaposi’s recognition in 1872 of the systemic manifestations of the disease. Kaposi wrote, “… experience has shown that lupus erythematosus (“erythematosus” is Latin for red) … may be attended by altogether more severe pathological changes … and even dangerous constitutional symptoms may be intimately associated with the process in question, and that death may result from conditions which must be considered to arise from the local malady.“ Kaposi proposed that there were two types of lupus erythematosus; the discoid form and a disseminated form. Furthermore, he enumerated various symptoms and signs which characterized the disseminated form including (1) subcutaneous nodules, (2) arthritis with synovial hypertrophy of both small and large joints, (3) lymphadenopathy, (4) fever, (5) weight loss, (6) anemia, and (7) central nervous system involvement. The existence of a systemic form of lupus was firmly established by the work of Osler in Baltimore and Jadassohn in Vienna in 1904.

The modern period began in 1948 with the discovery of the LE cell by Hargraves and colleagues. The investigators observed these cells in the bone marrow of patients with acute disseminated lupus erythematosus and postulated that the cell “… is the result of … phagocytosis of free nuclear material with a resulting round vacuole containing this partially digested and lysed nuclear material …“ This discovery ushered in the present era of the application of immunology to the study of lupus erythematosus. 

Two other immunologic markers were recognized in the 1950s as being associated with lupus: the biologic false-positive test for syphilis12 and the immunofluorescent test for antinuclear antibodies. Medical historians have theorized that people with porphyria (a disease that shares many symptoms with SLE) generated folklore stories of vampires and werewolves, due to the photosensitivity, scarring, hair growth, and porphyrin brownish-red stained teeth in severe recessive forms of porphyria (or combinations of the disorder, known as dual, homozygous, or compound heterozygous porphyrias). 

Useful medication for the disease was first found in 1894, when quinine was first reported as an effective therapy. Four years later, the use of salicylates in conjunction with quinine was noted to be of still greater benefit. This was the best available treatment until the middle of the twentieth century, when the treatment of systemic lupus was revolutionized by the discovery of the efficacy of adrenocorticotrophic hormone and cortisone by Hench. Corticosteroids have been the primary therapy for almost all patients with systemic lupus. Antimalarials have been used principally for patients with skin and joint involvement on the one hand and cytotoxic/immunosuppressive drugs have been used for patients with glomerulonephritis, systemic vasculitis, and other severe life-threatening manifestations on the other.

Two other major advances in the modern era have been the development of animal models of lupus and the recognition of the role of genetic predisposition to the development of lupus. The familial occurrence of systemic lupus was first noted by Leonhardt in 1954 and later studies by Arnett and Shulman at Johns Hopkins. Subsequently, familial aggregation of lupus, the concordance of lupus in monozygotic twin pairs, and the association of genetic markers with lupus have been described.

Folate Promotes Healing In Spinal Cord Injuries

Nearly 11,000 Americans experience a spinal cord injury each year. The effects of spinal cord injury vary with the extent of the injury, with severe injuries resulting in complete paralysis below the injury site. Folate, a B vitamin, occurs naturally in leafy green vegetables and other foods. The synthetic form, folic acid, is used to supplement cereal grains in the United States. The vitamin is important for the formation of the brain and spinal cord in the early embryo. The U. S. Public Health Service recommends that all women of childbearing age consume 400 micrograms of folic acid each day to reduce their risk of having a child with a neural tube defect, a birth defect of the brain and spinal cord. According to an article published in the Journal of Clinical Investigation (2010;120:1603-1616), the vitamin folate appears to promote healing in damaged rat spinal cord tissue by triggering a change in DNA. The study showed that the healing effects of the vitamin increased with the dosage, until regrowth of the damaged tissue reached a maximum level. After this threshold was reached, regrowth declined progressively with increasing doses until it reached the level seen in the absence of the vitamin. Specifically, folate stimulated a process known as DNA methylation, a natural biochemical process in which chemical compounds known as methyl groups are attached to DNA. The study results suggest that a greater understanding of the chemical sequences associated with folate metabolism and DNA methylation may lead to new techniques to promote healing of damaged spinal cords and other nervous system injuries. The research is at an early stage and additional studies are needed to determine what role folate might play in the treatment of human beings with spinal cord injury. Because of folate’s role in fetal spinal cord development, the study sought to determine if the vitamin could promote healing in damaged adult nervous system tissue. In a previous study, the researchers showed that folate could enhance the regrowth of axons, or nerve fibers, in rats with spinal cord injuries. To understand how folate helps repair damaged axons, the authors undertook additional observations. They found that injured nerve tissue began producing surface receptors for folate. Folate fits into the receptors, like a key fits into a lock, and then is absorbed into the nerve cell. After folate was absorbed into injured nervous system tissue, the nerve cells began producing enzymes that attach methyl groups to DNA. Chemically blocking folate from binding to the nerve cells, or blocking the methylation enzymes, hindered the nerve healing process. The study also tested the methylation of spinal cord DNA at various doses of folate and found that, like the regrowth of axons, DNA methylation peaked at a dose of 80 micrograms folate per kilogram of body weight.

Association Between Adiposity in Midlife and Older Age and Risk of Diabetes in Older Adults

Adiposity is a well-recognized risk factor for type 2 diabetes among young and middle-aged adults, but the relationship between body composition and type 2 diabetes is not well described among older adults. As a result, a study published in the Journal of the American Medical Association (2010;303:2504-2512) was performed to examine the relationship between adiposity, changes in adiposity, and risk of incident type 2 diabetes in adults 65 years and older. The investigation was a prospective cohort study (1989-2007) of 4,193 men and women 65 years of age and older in the Cardiovascular Health Study. Measures of adiposity were derived from anthropometry and bioelectrical impedance data at baseline and anthropometry repeated 3 years later. The main outcome measure was Incident diabetes based on use of antidiabetic medication or a fasting glucose level of 126 mg/dL or greater. Results showed that over median follow-up of 12.4 years (range, 0.9-17.8 years) there were 339 cases of incident diabetes (7.1/1000 person-years). The adjusted hazard ratio (HR) of type 2 diabetes for participants in the highest fifth of baseline measures compared with those in the lowest fifth was 4.3 for body mass index (BMI), 3.0 for BMI at 50 years of age, 4.2  for weight, 4.0 for fat mass, 4.2 for waist circumference, 2.4 for waist-hip ratio, and 3.8 for waist-height ratio. However, when stratified by age, participants 75 years of age and older had HRs approximately half as large as those 65 to 74 years of age. Compared with weight-stable participants (+ 2 kg), those who gained the most weight from 50 years of age to baseline (9 kg), and from baseline to the third follow-up visit (6 kg), had HRs for type 2 diabetes of 2.8 and 2.0, respectively. Participants with a greater than 10-cm increase in waist size from baseline to the third follow-up visit had an HR of type 2 diabetes of 1.7 (95% CI, 1.1-2.8) compared with those who gained or lost 2 cm or less. According to the authors, among older adults, overall and central adiposity, and weight gain during middle age and after the age of 65 years are associated with risk of diabetes.

Tooth Brushing, Inflammation, and Risk of Cardiovascular Disease

According to an article published in the British Medical Journal (2010;340:c2451), a study was performed to examine if self reported tooth brushing behavior is associated with cardiovascular disease and markers of inflammation (C reactive protein) and coagulation (fibrinogen). Study subjects were 11,869 men and women, mean age 50 years of age, who participated in the Scottish Health Survey, which draws a nationally representative sample of the general population living in households in Scotland. The main outcome measure was oral hygiene assessed from self reported frequency of tooth brushing. The association between oral hygiene and inflammatory markers and coagulation was examined in a subsample of participants (n=4,830). During the course of the study, there were a total of 555 cardiovascular disease events over an average of 8.1 years of follow-up, of which 170 were fatal. Of 411 (74%) of cardiovascular disease events, the principal diagnosis was coronary heart disease. Participants who reported poor oral hygiene (never/rarely brushed their teeth) had an increased risk of a cardiovascular disease event (hazard ratio 1.7; P<0.001) in a fully adjusted model. They also had increased concentrations of both C reactive protein and fibrinogen. According to the authors, poor oral hygiene is associated with higher levels of risk of cardiovascular disease and low grade inflammation, though the causal nature of the association is yet to be determined.

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 FDA Approves First Diagnostic Assay to Detect Both HIV Antigen and Antibodies

 Target Health is pleased to announce that Target e*CRF® was used for this program.

 HIV is the virus that can lead to acquired immune deficiency syndrome, or AIDS. HIV damages a person’s body by destroying specific blood cells, called CD4+ T cells, which are crucial to helping the body fight diseases. Two types of HIV have been identified: HIV-1 and HIV-2. HIV-1 is responsible for most HIV infections throughout the world. HIV-2 is found primarily in West Africa; however, cases of HIV-2 infection have been reported in North America and Europe. The Centers for Disease Control and Prevention report that approximately 18 million people in the United States are tested for HIV each year. Most recent CDC estimates are that there are about 56,000 new HIV infections in the United States each year. In addition, there are more than 1 million people living with HIV in the United States, according to CDC.

 FDA has approved the first assay to detect both antigen and antibodies to Human Immunodeficiency Virus (HIV). This assay is approved for use as an aid in the diagnosis of HIV-1/HIV-2 infection in adults including pregnant women. It is also the first assay for use as an aid in the diagnosis of HIV-1/HIV-2 infection in children as young as two years old. The highly sensitive assay is intended to be used as an aid in the diagnosis of HIV-1/HIV-2 infection, including acute or primary HIV-1 infection. Since it actually detects the HIV-1 virus (specifically the p24 antigen) in addition to antibodies to HIV, the ARCHITECT HIV Ag/Ab Combo assay can be used to diagnose HIV infection prior to the emergence of antibodies. Most tests used today in the diagnostic setting detect HIV antibodies only. Although direct detection of the virus itself by nucleic acid testing is available, it is not widely used in diagnostic settings. The ARCHITECT HIV Ag/Ab Combo assay is not intended to be used for routine screening of blood donors. However, it is approved as a donor screening assay for HIV-1/HIV-2 infection in urgent situations where licensed blood donor screening tests are unavailable or their use is impractical. The ARCHITECT HIV Ag/Ab Combo assay will be used in clinical laboratories and in public health laboratories, and is the first assay approved in the United States to detect HIV antigen and antibodies simultaneously. The ARCHITECT HIV Ag/Ab Combo assay is manufactured by Abbott Laboratories, Abbott Park, Illinois.

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